Modeling to Support Dose Justification for Anti-PD-L1 Clinical Candidate CK-301 in Oncology Patients

Collaboration with Checkpoint Therapeutics - Presented at SITC Annual Meeting 2019


Background: Mathematical modeling was used in conjunction with in vitro, preclinical and clinical data to facilitate dose selection of CK-301 (also known as TG-1501), an anti-PD-L1 monoclonal antibody (mAb), for ongoing and future clinical trials in oncology patients.

Methods: A semi-mechanistic pharmacokinetic/target-occupancy (PKTO) model was developed to predict pharmacokinetics (PK) of CK-301 at steady state and its tumor target occupancy (TO) under various dosing regimens. The model captures the interactions between CK-301, PD-L1, soluble PD-L1 and PD-1 in 3 compartments: tumor, circulation (central) and other tissues (peripheral). The model was calibrated with CK-301 PK data from the first 5 patients in a clinical study, CK-301-101, and PK data from published Phase 1 studies of 3 marketed anti-PD-L1 mAbs: atezolizumab, avelumab and durvalumab. Additionally, the model incorporated experimentally determined binding affinities for the 3 marketed anti-PD-L1 mAbs and CK-301.

Results: Using the PKTO model, plasma Ctrough values and tumor TO of CK-301 at steady-state with 800 and 1200 mg q2w or q3w were projected. The TO of CK-301 were compared with predicted steady-state Ctrough TOs of atezolizumab, avelumab and durvalumab at their marketed doses. The steady-state Ctrough values of CK-301 are predicted to give >99% tumor TO for patients with a nominal or a 10-fold greater than nominal PD-L1 tumor burden. This is similar to predicted TO for atezolizumab and durvalumab. The PKTO model was used to simulate PK and TO of CK-301 in 1000 virtual patients. The simulations predicted that, at 800 and 1200 mg q2w or q3w, 93.0% of patients with a nominal PD-L1 tumor burden or 80.1% of patients with 10-fold higher than nominal PD-L1 tumor burden would have a >99% tumor TO at steady-state Ctrough.

Conclusions: At the proposed CK-301 dosing regimens of 800 and 1200 mg q2w or q3w, a >99% TO is expected throughout the dosing interval. Relative to atezolizumab and durvalumab treatments, similar percentages of patients would possibly benefit from CK-301 treatment.

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